The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with (90)yttrium ((90)Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6-97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients. With a median follow-up of 65.6 months (range 4.0-96.5), the median progression-free survival (PFS) was 47.6 months (range 4.0-93.3) and median overall survival (OS) was not reached. The 5-year PFS was 40% (90% CI: 19.9-59.5%) and 5-year OS was 71.8% (90% CI: 46.8-86.5%). Overall, (90)Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates.